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J. Biol. Chem., Vol. 277, Issue 7, 4704-4712, February 15, 2002
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From the Department of Biochemistry and Biophysics, and the Johnson
Research Foundation, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania 19104-6059
Members of the epidermal growth factor
receptor, or ErbB, family of receptor tyrosine kinases have a
single transmembrane (TM)
The Single Transmembrane Domains of ErbB Receptors
Self-associate in Cell Membranes*
,
-helix that is usually assumed to play a
passive role in ligand-induced dimerization and activation of the
receptor. However, recent studies with the epidermal growth factor
receptor (ErbB1) and the erythropoietin receptor have indicated that
interactions between TM -helices do contribute to stabilization of
ligand-independent and/or ligand-induced receptor dimers. In addition,
not all of the expected ErbB receptor ligand-induced dimerization
events can be recapitulated using isolated extracellular domains,
suggesting that other regions of the receptor, such as the TM domain,
may contribute to dimerization in vivo. Using an approach
for analyzing TM domain interactions in Escherichia coli
cell membranes, named TOXCAT, we find that the TM domains of ErbB
receptors self-associate strongly in the absence of their extracellular
domains, with the rank order ErbB4-TM > ErbB1-TM 
ErbB2-TM > ErbB3-TM. A limited mutational analysis suggests that
dimerization of these TM domains involves one or more
GXXXG motifs, which occur frequently in the TM
domains of receptor tyrosine kinases and are critical for stabilizing the glycophorin A TM domain dimer. We also analyzed the effect of the
valine to glutamic acid mutation in ErbB2 that constitutively activates
this receptor. Contrary to our expectations, this mutation reduced
rather than increased ErbB2-TM dimerization. Our findings suggest a
role for TM domain interactions in ErbB receptor function, possibly in
stabilizing inactive ligand-independent receptor dimers that have been
observed by several groups.
*
This work was supported in part by National Institutes of
Health Grant R01-CA79992 and United States Army Breast Cancer Research Program Grant DAMD17-98-1-8232.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
American Cancer Society Jean and Harold Grossman Fellow (Grant
PF-00-174-01-TBE).
§
To whom correspondence should be addressed: Dept. of Biochemistry & Biophysics, University of Pennsylvania School of Medicine, 809C
Stellar-Chance Laboratories, 422 Curie Blvd., Philadelphia, PA
19104-6059. Tel.: 215-898-3072; Fax: 215-573-4764; E-mail: mlemmon@mail.med.upenn.edu.
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